In a letter to the editor in Pediatric Blood & Cancer, researchers presented the rare case of hepatoblastoma in a syndromic child who was found to have a de novo germline JAG1 mutation that did not quite meet the criteria for Alagille syndrome (ALGS).

A male child presented with global developmental defects, facial dysmorphism, and a congenital heart defect—in this case, the patient had scimitar syndrome with total anomalous pulmonary venous return. The patient was also found to have developed hepatoblastoma, which ultimately resulted in a fatal outcome. 

At 2 years of age, a repeat physical examination revealed craniofacial dysmorphism and a holosystolic heart murmur. In addition, he had abdominal distention, an umbilical hernia, and prominent calcanei. A tumor analysis revealed a high-risk mixed epithelial-mesenchymal hepatoblastoma, PRETEXT 4; sadly, the patient passed away after 1 month of etoposide treatment. 

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The patient had a male twin brother (diamniotic and dichorionic pregnancy) who presented with the same cardiac anomaly and died during cardiac surgery. An exome analysis of the proband revealed a heterozygous de novo frameshift 4-bp deletion in exon 26 of the JAG1 gene, thought likely to be pathogenic.

Read more about ALGS diagnosis 

Cardiovascular complications are a common feature of individuals with JAG1 mutations; they are seen in up to 80% of patients. One of the most common cardiac manifestations of these mutations is tetralogy of Fallot. 

In the main patient in this case study, bile duct paucity was not detected, despite it being one of the most common signs of ALGS. However, it should be noted that the boy’s physicians were unable to complete a full investigation into associated anomalies due to his critical condition. Nevertheless, the lack of bile duct paucity and other extracardiac features meant that the patient fell short of the full clinical spectrum commonly observed in patients with ALGS. 

“Therefore, this case implicates JAG1 as a candidate gene for scimitar syndrome and/or total anomalous pulmonary venous return, and reinforces the association of JAG1 with hepatoblastoma risk, thus expanding the set of genes linked to hepatoblastoma susceptibility,” the authors wrote. 


Dangoni GD, Teixeira ACB, Aguiar TF, et al. A rare case of hepatoblastoma in a syndromic child with a de novo germline JAG1 mutationPediatr Blood Cancer. Published online March 25, 2023. doi:10.1002/pbc.30311